Down Syndrome Critical Region 1 Gene,
            <i>Rcan1</i>
            , Helps Maintain a More Fused Mitochondrial Network

Parra, Valentina; Altamirano, Francisco; Hernández‐Fuentes, Carolina; Tong, Dan; Kyrychenko, Viktoriia; Rotter, David; Pedrozo, Zully; Hill, Joseph A.; Eisner, Verónica; Lavandero, Sergio; Schneider, Jay W.; Rothermel, Beverly A.

doi:10.1161/circresaha.117.311522

Cited by 51 publications

(69 citation statements)

References 52 publications

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“…We have recently shown that loss of RCAN1 increases calcineurin-dependent mitochondrial fission both in vitro and in vivo [78]. Consistent with increased fission, we found that mitochondrial membrane potential and oxygen consumption were lower in myocytes and fibroblasts isolated from Rcan1-KO mice.…”

Section: Rcan1 Acts In Multiple Tissuessupporting

confidence: 86%

Regulator of Calcineurin 1 helps coordinate whole‐body metabolism and thermogenesis

et al. 2018

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Increasing non‐shivering thermogenesis (NST), which expends calories as heat rather than storing them as fat, is championed as an effective way to combat obesity and metabolic disease. Innate mechanisms constraining the capacity for NST present a fundamental limitation to this approach, yet are not well understood. Here, we provide evidence that Regulator of Calcineurin 1 (RCAN1), a feedback inhibitor of the calcium‐activated protein phosphatase calcineurin (CN), acts to suppress two distinctly different mechanisms of non‐shivering thermogenesis (NST): one involving the activation of UCP1 expression in white adipose tissue, the other mediated by sarcolipin (SLN) in skeletal muscle. UCP1 generates heat at the expense of reducing ATP production, whereas SLN increases ATP consumption to generate heat. Gene expression profiles demonstrate a high correlation between Rcan1 expression and metabolic syndrome. On an evolutionary timescale, in the context of limited food resources, systemic suppression of prolonged NST by RCAN1 might have been beneficial; however, in the face of caloric abundance, RCAN1‐mediated suppression of these adaptive avenues of energy expenditure may now contribute to the growing epidemic of obesity.

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Section: Rcan1 Acts In Multiple Tissuessupporting

confidence: 86%

Regulator of Calcineurin 1 helps coordinate whole‐body metabolism and thermogenesis

et al. 2018

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“…Several lines of evidence suggest that RCAN1 is involved in the regulation of mitochondrial function in different cell types [19][20][21]. However, the role of RCAN1 in renal cells is still unknown.…”

Section: Discussionmentioning

confidence: 99%

“…RCAN1 overexpression also promotes age-dependent mitochondrial dysregulation and progressive neurodegeneration in Alzheimer's disease [20]. On the other hand, mitochondrial function is reduced in cardiomyocytes depleted of RCAN1, and increasing RCAN1.1 level helps maintain a more fused mitochondrial network and increase O 2 consumption [21]. These contrary regulatory effects suggest that more in-depth studies are needed on how RCAN1 works.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that RCAN1 is involved in the regulation of mitochondrial function. Increased RCAN1 expression results in impaired mitochondrial function in β cells and neuronal cells [19,20], but high RCAN1 in cardiomyocytes generates a more fused mitochondrial network and enhances mitochondrial function [21]. These contradictory results suggest that the functions of RCAN1 related to the regulation of mitochondrial function appear to be dependent on cell type and the type of stimuli.…”

Section: Introductionmentioning

confidence: 99%

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RCAN1.4 mediates high glucose-induced matrix production by stimulating mitochondrial fission in mesangial cells

et al. 2020

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High glucose (HG)-induced mitochondrial dynamic changes and oxidative damage are closely related to the development and progression of diabetic kidney disease (DKD). Recent studies suggest that regulators of calcineurin 1 (RCAN1) is involved in the regulation of mitochondrial function in different cell types, so we investigate the role of RCAN1 in mitochondrial dynamics under HG ambience in rat glomerular mesangial cells (MCs). MCs subjected to HG exhibited an isoform-specific up-regulation of RCAN1.4 at both mRNA and protein levels. RCAN1.4 overexpression induced translocation of Dynamin related protein 1 (Drp1) to mitochondria, mitochondrial fragmentation and depolarization, accompanied by increased matrix production under normal glucose and HG ambience. In contrast, decreasing the expression of RCAN1.4 by siRNA inhibited HG-induced mitochondrial fragmentation and matrix protein up-regulation. Moreover, both mitochondrial fission inhibitor Mdivi-1 and Drp1 shRNA prevented RCAN1.4-induced fibronectin up-regulation, suggesting that RCAN1.4-induced matrix production is dependent on its modulation of mitochondrial fission. Although HG-induced RCAN1.4 up-regulation was achieved by activating calcineurin, RCAN1.4-mediated mitochondrial fragmentation and matrix production is independent of calcineurin activity. These results provide the first evidence for the HG-induced RCAN1.4 up-regulation involving increased mitochondrial fragmentation, leading to matrix protein up-regulation.

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“…AAC could influence cell death through a cooperation with pro-apoptotic proteins, such as Bax, or through its participation in the MPTP complex [ 64 , 77 ]. Alteration of AAC activity has been reported in Drosophila nebula mutants [ 78 , 79 ] Nebula is the Drosophila homolog of human Down syndrome critical region gene 1 (DSCR1), one of the genes involved in the establishment of the phenotype associated with Down syndrome. DSCR1 overexpression in Down syndrome fetal brain tissue seems to contribute to mental retardation in Down syndrome patients.…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

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Lunetti

Zara

et al. 2020

IJMS

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Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.

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Down Syndrome Critical Region 1 Gene, Rcan1 , Helps Maintain a More Fused Mitochondrial Network

Abstract: RCAN1 helps maintain a more interconnected mitochondrial network, and maintaining appropriate RCAN1 levels is important to human health and disease.

Cited by 51 publications

References 52 publications

Regulator of Calcineurin 1 helps coordinate whole‐body metabolism and thermogenesis

Regulator of Calcineurin 1 helps coordinate whole‐body metabolism and thermogenesis

RCAN1.4 mediates high glucose-induced matrix production by stimulating mitochondrial fission in mesangial cells

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

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